We are interested in chromatin remodelling factors in human disease and in particular the function of one, ATRX. Germline mutations in ATRX lead to an X-linked syndrome associated with severe intellectual disability and alpha thalassaemia, ATR-X syndrome; somatic mutations are observed in 5-10% of cancers.
One of the major challenges in the post-genomic era is to understand the factors that regulate and facilitate gene expression. It has become apparent that the regulation of chromatin structure is of paramount importance in not only gene expression but a wide variety of fundamental nuclear processes including DNA replication, repair and recombination. The ATP-dependent chromatin remodelling factor ATRX (α thalassaemia/mental retardation X-linked) has emerged as a key player in each of these processes. The principal aim of the group is to characterise the ATRX protein which, when mutated, gives rise to a severe X-linked form of syndromal intellectual disability, one feature of which is alpha thalassaemia. More recently, we have shown that somatic mutations in this gene give rise to an acquired form of alpha thalassaemia associated with myelodysplasia. ATRX mutations are also almost invariantly found in a group of cancers that maintain their telomeres by a telomerase-independent mechanism called the Alternative Lengthening of Telomere (ALT) pathway. Work from our lab and others suggest that ATRX plays a variety of key roles at tandem repeat sequences within the genome, including deposition of a histone variant, the maintenance of chromatin marks, prevention of replication fork stalling, and the suppression of the homologous recombination-based ALT pathway of telomere maintenance. The purpose of our work is to determine the role of this protein in the nucleus and how mutations give rise to seemingly disparate disorders.
David Clynes, Children with Cancer UK
Paul O’Gorman, Research Fellow, Weatherall Institute of Molecular Medicine
Clinical studies and trials
We run a clinical and molecular diagnostic service through which we have collected over 200 affected families. We identify the underlying mutations and through gene expression analysis, methylation studies, enzyme assays and protein structure studies we are defining their functional consequences.